The present invention relate to oligomers and oligonucleotides that can bind to complementary RNA. Oligonucleotides are useful as reagents in science, research and development e.g. for detection and analysis of cellular RNA or for modulation of the activity of cellular RNA.
Oligonucleotides are also being developed as therapeutics, where they are typically also intended to bind to and modulate the activity of cellular RNA. Oligonucleotides that bind cellular RNA are herein also termed antisense oligonucleotides.
Some antisense oligonucleotides act by inducing destabilization of their target RNA e.g. by activating RNase H degradation of the target RNA or by activating the RISC pathway. Such oligonucleotides are typically described as gapmers and siRNAs respectively. Another class of oligonucleotides act as steric blocker and hence prevents the target RNA from interacting with another macromolecule. One example is splice switching oligonucleotides that modulate splicing of pre-mRNA. Another example is microRNA inhibitors that bind to microRNA and prevent the microRNA from binding to its mRNA targets. A thorough description of the design, preparation and use of antisense oligonucleotides can be found in “Antisense Drug Technology, Principles, Strategies and Applications, 2nd Edition, Edited by Stanley Crooke”.
It is easy to design an antisense oligonucleotide that is complementary to a given target RNA and hence is capable of binding to the target RNA. However, when attempting to develop antisense oligonucleotides as therapeutics, complementarity to the target is not enough. The antisense oligonucleotide need to be modified to give it more drug-like properties, e.g. better potency, bioavailability and biostability. Moreover, it has turned out that a problem of many antisense oligonucleotides is off-target binding, i.e. binding to non-intended RNAs, which may lead to undesirable effects. To minimize off-target binding, it is typically attempted to target unique sequences in the RNA transcriptome. Even so, off-target binding of antisense oligonucleotides is still a problem. One object of the present invention is to provide antisense oligonucleotides, in particular steric block oligonucleotides that have new and desirable characteristics in terms of off-target binding.